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Involvement of calcium-mediated apoptotic signals in H2O2-induced MIN6N8a cell death.

Authors
Choi, SE; Min, SH; Shin, HC; Kim, HE; Jung, MW; Kang, Y
Citation
European journal of pharmacology, 547(1-3):1-9, 2006
Journal Title
European journal of pharmacology
ISSN
0014-29991879-0712
Abstract
Reactive oxygen species are believed to be the central mediators of beta-cell destruction that leads to type 1 and 2 diabetes, and calcium has been reported to be an important mediator of beta cell death. In the present study, the authors investigated whether Ca(2+) plays a role in hydrogen peroxide (H(2)O(2))-induced MIN6N8a mouse beta cell death. Treatment with low concentration H(2)O(2) (50 microM) was found to be sufficient to reduce MIN6N8a cell viability by 55%, largely via apoptosis. However, this H(2)O(2)-induced cell death was near completely blocked by pretreatment with BAPTA/AM (5 microM), a chelator of intracellular Ca(2+). Moreover, the intracellular calcium store channel blockers, such as, xestospongin c and ryanodine, significant protected cells from 50 microM H(2)O(2)-induced cell death and under extracellular Ca(2+)-free conditions, 50 microM H(2)O(2) elicited transient [Ca(2+)](i) increases. In addition, pharmacologic inhibitors of calpain, calcineurin, and calcium/calmodulin-dependent protein kinase II were found to have a protective effect on H(2)O(2)-induced death. Moreover, H(2)O(2)-induced apoptotic signals, such as c-JUN N-terminal kinase activation, cytochrome c release, caspase 3 activation, and poly (ADP-ribose) polymerase cleavage were all down-regulated by the intracellular Ca(2+) chelation. These findings show that [Ca(2+)](i) elevation, possibly due to release from intracellular calcium stores and the subsequent activation of Ca(2+)-mediated apoptotic signals, critically mediates low concentration H(2)O(2)-induced MIN6N8a cell death. These findings suggest that a breakdown of calcium homeostasis by low level of reactive oxygen species may be involved in beta cell destruction during diabetes development.
MeSH terms
AnimalsApoptosis/drug effects*Calcineurin/antagonists & inhibitorsCalcineurin/metabolismCalcium/antagonists & inhibitorsCalcium/metabolism*Calpain/antagonists & inhibitorsCalpain/metabolismCaspase 3/metabolismCell Line, TumorCell Survival/drug effectsChelating Agents/pharmacologyEgtazic Acid/analogs & derivativesEgtazic Acid/pharmacologyEnzyme Activation/drug effectsEnzyme Inhibitors/pharmacologyHydrogen Peroxide/toxicity*Insulinoma/metabolismInsulinoma/pathologyIntracellular Fluid/drug effectsIntracellular Fluid/metabolismJNK Mitogen-Activated Protein Kinases/metabolismMacrocyclic Compounds/pharmacologyOxazoles/pharmacologyOxidants/toxicityPoly(ADP-ribose) Polymerases/metabolismRyanodine/pharmacologySignal Transduction/drug effects*
DOI
10.1016/j.ejphar.2006.06.016
PMID
16934799
Appears in Collections:
Journal Papers > Research Organization > Institute for Medical Sciences
Journal Papers > Research Organization > Chronic Inflammatory Disease Research Center
Journal Papers > School of Medicine / Graduate School of Medicine > Physiology
AJOU Authors
최, 성이정, 민환강, 엽
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